The sulfatase deficiency disorders include a number of lysosomal storage diseases and are a significant cause of mental retardation and physical deformities. Since the biochemical and enzymic basis for these disorders have been defined, an important facet of these diseases necessary for diagnostic and therapeutic strategies is the determination of the metabolism of the enzymes involved. Multiple sulfatase deficiency (MSD) is a unique genetic disorder resulting from deficiencies of at least seven distinct sulfatases and appears to result from either defective control of enzymic synthesis or a previously unknown cause of increased degradation of cellular enzymes. The comparison of metabolism of a number of sulfatases in MSD cells with normal or single sulfatase deficiency cells is likely to produce new knowledge of control of levels of cellular hydrolases. The proposed studies will use cultured cells as a source of material. All of the sulfatases will be compared enzymatically to determine what common factors may be necessary for stability of sulfatases, with a view toward defining cellular processes necessary to maintain normal enzyme levels. A major emphasis will be to use antibodies to sulfatases, in particular iduronate sulfatase (IdS-S), to measure rates of synthesis and degradation of this enzyme in cultured cells. If pulse-chase labeling experiments indicate that enzyme degradation is the major defect in MSD, the steps involved in post-translational processing and transport will be investigated. If decreased rates of synthesis are indicated, the factors controlling synthesis, including amounts of translatable mRNA, will be determined. Such probes can also be used for the study of Hunter syndrome (IdS-S deficiency) and its variants and may lead to information about the pathogenesis of mental retardation in this disease. Finally, a genetic approach to the understanding of MSD will be utilized. Established rodent cell lines will be mutagenized and screened for mutants having the MSD phenotype and those which appear to have a genetic defect similar to MSD, as evidenced by lack of complementation in MSD-rodent cell hybrids will be analyzed. Among the uses of such mutants will be the mapping of the human gene responsible for correcting the MSD phenotype to a specific human chromosome. This combination of metabolic studies and genetic analysis is likely to lead to better definition of the controls involved in maintenance of cellular enzyme levels.